Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency.
View / Open Files
Authors
Moore, Stephen D
Jafri, Salema
Mitchell, Melissa
Brady, Hugh JM
Mandelboim, Ofer
Southwood, Mark
Morrell, Nicholas W
Colucci, Francesco
Ormiston, Mark L
Publication Date
2018-12-01Journal Title
Am J Physiol Lung Cell Mol Physiol
ISSN
1040-0605
Publisher
American Physiological Society
Volume
315
Issue
6
Pages
L977-L990
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Rätsep, M. T., Moore, S. D., Jafri, S., Mitchell, M., Brady, H. J., Mandelboim, O., Southwood, M., et al. (2018). Spontaneous pulmonary hypertension in genetic mouse models of natural killer cell deficiency.. Am J Physiol Lung Cell Mol Physiol, 315 (6), L977-L990. https://doi.org/10.1152/ajplung.00477.2017
Abstract
Natural killer (NK) cells are cytotoxic innate lymphoid cells with an established role in the regulation of vascular structure in pregnancy and cancer. Impaired NK cell function has been identified in patients with pulmonary arterial hypertension (PAH), a disease of obstructive vascular remodeling in the lungs, as well as in multiple rodent models of disease. However, the precise contribution of NK cell impairment to the initiation and progression of PAH remains unknown. Here, we report the development of spontaneous pulmonary hypertension in two independent genetic models of NK cell dysfunction, including Nfil3-/- mice, which are deficient in NK cells due to the absence of the NFIL3 transcription factor, and Ncr1-Gfp mice, which lack the NK activating receptor NKp46. Mouse models of NK insufficiency exhibited increased right ventricular systolic pressure and muscularization of the pulmonary arteries in the absence of elevated left ventricular end-diastolic pressure, indicating that the development of pulmonary hypertension was not secondary to left heart dysfunction. In cases of severe NK cell impairment or loss, a subset of mice failed to develop pulmonary hypertension and instead exhibited reduced systemic blood pressure, demonstrating an extension of vascular abnormalities beyond the pulmonary circulation into the systemic vasculature. In both mouse models, the development of PAH was linked to elevated interleukin-23 production, whereas systemic hypotension in Ncr1-Gfp mice was accompanied by a loss of angiopoietin-2. Together, these results support an important role for NK cells in the regulation of pulmonary and systemic vascular function and the pathogenesis of PAH.
Keywords
Th17, angiopoietin-2, interleukin-23, natural killer cells, pulmonary hypertension, Animals, Basic-Leucine Zipper Transcription Factors, Disease Models, Animal, Endothelial Cells, Humans, Hypertension, Pulmonary, Killer Cells, Natural, Lung, Mice, Natural Cytotoxicity Triggering Receptor 1, Pulmonary Artery, Vascular Remodeling
Sponsorship
Wellcome Trust (200841/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1152/ajplung.00477.2017
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285686
Rights
Licence:
http://www.rioxx.net/licenses/all-rights-reserved
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk